Sphingosine 1-phosphate (S1P) is a natural sphingolipid that functions as an intramolecular messenger in many types of cells and as an extracellular signalling molecule (for a recent review see Cooke et al, Annual Reports in Medicinal Chemistry, 2007, 42, pp 245-263 and references therein). The cellular effects induced by S1P are associated with platelet aggregation, cell morphology and proliferation, tumour cell invasion, endothelial cell chemotaxis and in vitro angiogenesis. The extracellular signalling occurs through interaction of S1P with G-protein-coupled receptors S1P1, S1P2, S1P3, S1P4 and S1P5. The intracellular activity of S1P and modulators has not been fully explored. S1P and its target have an essential role in lymphocyte migration through secondary lymphoid organs such the spleen, lymph nodes and mucosa-associated tissues such as the tonsils and Peyer's patches. The lymphocytes move from the peripheral circulation into the lymph nodes and mucosa associated tissues in order to generate immune responses. T and B lymphocytes are effectively sequestered within the thymus and secondary lymphoid tissue. Essentially, S1P and its receptor subtype −1 are required for lymphocytes to move out of the thymus and secondary lymphoid organs.
S1P type molecular modulators have been shown to be effective in multiple animal disease models. The S1P signalling, mainly through its receptor subtype −1, is important in halting the Treg response and has been recommended for immunotherapy of cancer and infectious disease (Liu, G., et al, Nature Immunology, 2009, 10, 769-777; Wolf, A. M., et al, J. Immunology, 2009, 183, 3751-60). The S1P mediated trans-activation of insulin receptor has been reported to help treat insulin resistance and type 2 diabetes (Rapizzi E. et al, Cell Mol. Life. Sci., 2009, 66, 3207-18). S1P1 receptor axis has a role in the migration of neural stem cells toward the site of spinal cord injury (Kimura, A., et al, Stem Cells, 2007, 25, 115-24). The S1P and its modulators supports the trafficking of hematopoietic progenitor cells and are helpful in tissue repair in myocardial infarction (Seitz, G., et al, Ann. N.Y. Acad. Sci., 2005, 1044, 84-89; Kimura, et al, Blood, 2004, 103, 4478-86) and a have great potential applications in regenerative medicines. S1P receptors play a critical role in endothelial barrier enhancement and vasculature maturation (McVerry, B. J., et al, Journal of Cellular Biochemistry, 2004, 1075-85; Allende, M. L., et al, Blood, 2003, 102, pp 3665-7; Paik, J., et al, Genes and Development, 2004, 18, 2392-2403; Garcia, J. G. N., et al, J. Clinical Investigation, 2001, 689-701). The vasculature normalization helps the cytotoxic T cells to access the remote and inner part of the tumour (Hamzah J. et al, Nature, 2008, 453, pp 410-414). The lymphocyte egress and endothelial barrier function is mediated through S1P1 receptor (Brinkmann, et al, American J. of Transplantation, 2004, 4, 1019-25; McVerry B. J. et al, Cellular Signalling, 2005, 17, pp 131-39). S1P type modulation reduces ischemia reperfusion injuries (Lein, Y. H., et al, Kidney International, 2006, 69, 1601-8; Tsukada, Y. T. et al, J Cardiovascular Pharmocol, 2007, 50, 660-9). S1P1 signalling is critical in preventing inflammation induced vascular leakage (Niessen, F. et al, Blood, 2009, 113, 2859-66; Wang L et al, Microvascular Research, 2009, 77, 39-45; Lee, J. F., et al, Am. J. Physiol. Heart Circ. Physiol., 2009, 296, H33-H42). It also reduces a vascular leakage in models of acute lung injury (McVerry, B. J., et al, Am. J. of Respiratory and Critical Care Medicine, 2004, 170, 987-93). The S1P vasculo-protection effect, mediated by nitric oxide and prostacyclin (Rodriguez C et al, Thromb. Haemost., 2009, 101, 66-73), prevents the development of atherosclerotic lesions (Nofer, J. R. et al, Circulation, 2007, 115, 501-8; Tolle, M., et al, European J. Clin. Inv., 2007, 37, 17-9; Keul, P., et al, Arterioscler. Thromb. Vasc. Biol., 2007, 27, 607-13). S1P prevents tumour necrosis factor alpha mediated monocyte adhesion to endothelial cells, implicated in the pathology of arthrosclerosis and inflammatory diseases (Bolick, D. T. et al, Arterioscler. Thromb. Vasc. Biol, 2005, 25, 976-81). Recently reported targets of S1P includes the family of Histone Deacylases (HDACs) (Hait, N. C., et al, Science, 2009, 325, 125-7), which are known for their epigenetic role. The S1P has been reported to help treatment of the latent mycobacterium tuberculosis infection by promoting the processing and presentation of antigens (Santucci, M. B. et al, Biochem. Biophys. Res. Comm., 2007, 361, 687-93). Additionally, the S1P and its modulators have cardio protective effects (Means, C. K., et al, Cardiovascular Research; 2009, 82, 193-200; Hofmann, U., et al, Cardiovascular Research, 2009, 83, 285-93; Tao, R., et al, J Cardiovasc. Pharmacol., 2009, 53, 486-94) and the signalling axis of S1P are important in the treatment of myocardial infarction (Yeh, C. C., et al, Am. J. Physiol. Heart Circ. Physiol., 2009, 296, H1193-9). Thus, S1P like molecular modulators have a great developmental potential in wide range of cardiovascular medicines.
Fingolimod (2-amino-2-(2-[4-octylphenyl]ethyl)-1,3-propanediol) (FTY-720) is metabolised to a structural analogue of S1P and has been found to effect S1P receptors. The discovery of FTY-720 and its efficiency in animal models and clinical studies, related to many autoimmune diseases and cancer treatment, has resulted in research efforts into S1P receptors.

FTY-720 decreases peripheral blood lymphocyte counts (lymphopenia) reversibly, without impairing the effector function of the immune cells (Pinschewer, D. et al, J. Immunology, 2000, 164, 5761-70). FTY-720 is an emerging novel drug for Multiple Sclerosis (MS) (Kieseier, B. C., et al, Pharmacological Research, 2009, 60, 207-11; Brown, B. A., The Annals of Pharmacotherapy, 2007, 41, 1660-8) and has a direct cyto-protective and process extension effect in oligodendrocyte progenitors (Coelho, R. P. et al, J. Pharmacology and Experimental Therapeutics, 2007, 323, 626-35; Miron, V. E. et al, Ann. Neurol, 2008, 63, 61-71). It is effective against autoimmune related pathologies such as type-1 diabetes (Yang, Z., et al, Clin. Immunology, 2003, 107, 30-5), arthritis (Matsuura, et al, Inflamm. Res., 2000, 49, 404-10) and oxazolone stimulated colitis (Daniel, et al, Molecular Immunology, 2007, 44, 3305-16). FTY-720 interaction with cytosolic Phospholipase A2 and modulation of the eicosanoids synthesis (Payne S. G. et al; Blood, 2007, 109, pp 1077-1085) indicates its potential as anti-inflammatory and antinociceptive agents and a safe pain killer (Coste, O., et al, J. Cell Mol. Med., 2008, Vol 12, 995-1004). The anticancer activity of FTY-720 is well documented by in vitro apoptotic activity studies as well as numerous animal model studies. Apoptosis is the process of programmed cell death (PCD) that may occur in multicellular organisms. Programmed cell death involves a series of biochemical events leading to a characteristic cell morphology and death; in more specific terms, a series of biochemical events that lead to a variety of morphological changes, including blebbing, changes to the cell membrane such as loss of membrane asymmetry and attachment, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation. The apoptotic mechanism observed in hepatocellular carcinoma cell lines is linked to the activation of protein kinase C delta (PKC-δ) (Hung, J. H., et al, 2008, 68, 1204-12). The apoptotic activity of FTY-720 against chronic myelogenous leukaemia and Philadelphia chromosome positive acute lymphocytic leukaemia was reported to be due to its control of Protein Phosphates 2A (PP2A) (Neviani et al, J of Clinical Investigation, 2007, 117, 24-21). Phosphorylated form of FTY-720 is speculated to be an anti-metastasis drug (Meeteren, et al, Cancer Lett., 2008, 266, 203-8). FTY-720 inhibits vascular endothelial cell growth factor induced vascular permeability (Sanchez, T., et al, J. Biological Chem., 2003, 278, 47281-90), linked to an anticancer and anti-metastatic effect in animal models (Azuma, H., et al, Cancer Res, 2002, 1410-19; Chua, C-W., at al, Int. J Cancer, 2005, 117, 1039-48; LaMontange, K. et al, 2006, 66, 221-31). The anti-angiogenic effect of FTY-720 through its interaction with S1P receptor subtype −1, was described recently (Schmid, G., et al, J. Cellular Biochem., 2007, 101, 259-70). FTY-720 helps favourable central nervous system (CNS) gene expression and improves the blood brain barrier function (Foster, C. A., et al, Brain Pathology, 2009, 19, 254-66). A few days of treatment with FTY-720 leads to complete eradication of chronic viral infection of lymphocytic choriomeningitis (Lanier, et al, Nature, 2008, 894-899). Its anti-fibrotic activity was reported recently (Brunati, A. M., et al, Biochem. Biophys. Acta, 2008, 1783, 347-59; Delbridge, M. S., et al, Transplantation Proceedings, 2007, 39, 2992-6). FTY 720 inhibits development of atherosclerosis in low density lipoprotein receptor deficient mice (Nofer, J. R., et al, Circulation, 2007, 115, 501-8; Tolle, M. et al, European J. Clinical Investigation, 2007, 37, 171-79). FTY720 was effective in the treatment of cerebral ischemia in the mouse model (Czech, B., et al, Biochem. Biophys. Res. Comm., 2009, online), indicating the great potential of S1P receptors modulators in the wide range of cardiovascular medicine. The derivatives of FTY-720 were reported as pulmonary barrier enhancers and thus potential agents for the development of critical care medicines (Camp, S. M., et al, J. Pharmacol. Experimental Therapeutics, 2009, online).
Of the classical mimics of S1P, the amino alcohols and their respective monophosphates, amino phosphonates, amino acids, alkoxyamino alcohols and alkyl carboxylates appear to be the most effective S1P receptors modulators. While an in vivo phosphorylation of the hydroxyl group of FTY 720 appears to be necessary for the most effective extracellular signalling and agonistic effect upon binding to S1P1-5, the apoptotic effect is limited to its non-phosphorylated form.
S1P type modulators have been shown to have a favourable response in multiple disease models and this response has been successfully translated to humans. The best explored is FTY 720, which apart from acting through S1P receptors, interacts with several intracellular receptors. It is advantageous to provide alternatives to FTY 720 in order to produce compounds with a greater range of activity, and/or altered or enhanced specificity, and/or improved pharmacological properties or reduction in side effects such as bradycardia, headache, fatigue and/or flu-like symptoms.
It is desirable to provide alternatives to FTY 720 and in particular alternative compounds with improved properties and/or activity. For example, this could include compounds with a greater range of activity, altered or enhanced specificity, improved pharmacological properties or reduction in side effects.
In particular, it is desirable to provide novel compounds having S1P receptor modulating activity as well as apoptotic activity and/or anti proliferative action against cancer cells and other cell types (dual activity).
Throughout this specification, use of the terms “comprises” or “comprising” or grammatical variations thereon shall be taken to specify the presence of stated features, integers, steps or components but does not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof not specifically mentioned.